Download HIV Vaccine

So tell me,
this physician of whom
you were just speaking,
Is he a money maker,
an earner of fees,
or a healer of the sick?
Plato, The Republic
This formidable array of defense mechanisms
Allows HIV to avoid being suppressed by our immune system
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
Blocking Cytosine Deamination
How can we help
the body fight back?
This formidable array of defense mechanisms
Allows HIV to avoid being suppressed by our immune system
Integration and latency
Destruction of CD4+ T cells
Inaccessible epitopes
Antigenic escape
Downregulating MHC
Blocking Cytosine Deamination
How about an
AIDS vaccine?
Even 2,500 Years Ago,
People Knew Immunity Worked.
• Greek physicians
noticed that people who
survived smallpox
never got it again.
• The insight:
Becoming
infected by certain
diseases gives
immunity.
Fast forward 2300 years
Vaccination
• Edward Jenner 1796 :
Cowpox/Swinepox
• 1800’s Compulsory childhood
vaccination
Variolation was a huge advance
Smallpox
•1% v. 25% mortality
•Life-long immunity
• UK: 1700’s
• China 1950
• Pakistan/Afghanistan/Ethiopia
1970
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt
Smallpox
Smallpox presented many advantages that made this possible
• No animal reservoir
• Lifelong immunity
• Subclinical cases rare
• Infectivity does
not precede overt symptoms
• One Variola serotype
•
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt
As a result, after a world-wide effort
Smallpox
Smallpox was eliminated
as a human disease in 1979
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt
Other vaccines have followed,
making once feared diseases a thing of the past
Reported cases per 100000 population
100
Inactivated
(Salk) vaccine
Cases per 100,000
population United
States
10
Oral
vaccine
1
0.1
0.01
0.00
1
1950
1960
1970
1980
1990
How does vaccination work?
Expose the patient to an Antigen
• A live or inactivated substance (e.g.,
protein, polysaccharide) derived from a
pathogen (e.g bacteria or virus) capable
of producing an immune response
How does vaccination work?
Expose the patient to an Antigen
• A live or inactivated substance (e.g.,
protein, polysaccharide) derived from a
pathogen (e.g bacteria or virus)capable of
producing an immune response
If the patient is subsequently exposed
to infectious agent carrying this
Antigen they will mount a faster
immune response
It works like this
Patient exposed to pathogen
Carrying antigens A and B
Molecular Biology of the Cell Alberts et al
Vaccines can be divided
into two types
• Live attenuated
• Inactivated
Inactivated Vaccines
fall into different categories
Whole
• viruses
• bacteria
Fractional
• Individual proteins from pathogen
• Pathogen specific complex sugars
Live Attenuated Vaccines
have several advantages
• Attenuated (weakened) form of the
•
•
"wild" virus or bacterium
Can replicate themselves so the
immune response is more similar to
natural infection
Usually effective with one dose
Live Attenuated Vaccines
also have several disadvantages
•
Severe reactions possible
especially in
immune compromised
patients
•
Worry about recreating
a wild-type pathogen
that can cause disease
•
Fragile – must be
stored carefully
MMWR, CDC
A number of the vaccines you received
were live Attenuated Vaccines
• Viral
measles, mumps,
rubella, vaccinia,
varicella/zoster,
yellow fever, rotavirus,
intranasal influenza,
oral polio
• Bacterial BCG (TB), oral typhoid
Inactivated Vaccines are the
other option
Pluses
• No chance of recreating live pathogen
• Less interference from circulating antibody
than live vaccines
Inactivated Vaccines are the
other option
Minuses
• Cannot replicate and thus generally not as
•
•
effective as live vaccines
Usually require 3-5 doses
Immune response mostly antibody based
Inactivated Vaccines are also
a common approach today
Whole-cell vaccines
• Viral
polio, hepatitis A,
rabies, influenza*
• Bacterial
pertussis*, typhoid*
cholera*, plague*
*not used in the United States
Other Inactivated Vaccines
now contain purified proteins
rather than whole bacteria/viruses
• Proteins
hepatitis B, influenza,
acellular pertussis,
human papillomavirus,
anthrax, Lyme
• Toxins
diphtheria, tetanus
Sabin Polio Vaccine
Attenuated by passage in foreign host (monkey kidney cells)
Selection to grow in new host makes virus
less suited to original host
Sabin Polio Vaccine
Attenuated by passage in foreign host (monkey kidney cells)
Selection to grow in new host makes virus
less suited to original host
• Grows in epithelial cells
• Does not grow in nerves
• No paralysis
•Local gut immunity (IgA)
Salk Polio Vaccine
•
Formaldehyde-fixed
• No reversion
Polio Vaccine illustrates the pluses
and minuses of live vaccines
US: Sabin attenuated vaccine
~ 10 cases vaccine-associated polio per year =
1 in 4,000,000 vaccine infections
Scandinavia: Salk dead vaccine
• No gut immunity
• Cannot wipe out wt virus
pathmicro.med.sc.edu/ppt-vir/vaccine.ppt
Live virus generates a more complete immune response
Reciprocal virus antibody titer
51
2
Killed
(Salk)
Vaccine
Live
(Sabin)
Vaccine
Serum
IgG
Serum
IgG
12
8
32
Serum IgM
Serum
IgM
Serum
IgA
8
Serum
IgA
2
1
Nasal
IgA
Duodenal
IgA
Nasal and
duodenal
IgA
Vaccination
4
8
96
Days Vaccination
48
9
6
Modern molecular biology
has offered new approaches
to make vaccines
Modern molecular biology
has offered new approaches
to make vaccines
1. Clone gene from virus or bacteria
and express this protein antigen
in yeast, bacteria or
mammalian cells in culture
Modern molecular biology
has offered new approaches
to make vaccines
2. Clone gene from virus or bacteria
Into genome of another virus (adenovirus, canary pox, vaccinia)
And use this live virus as vaccine
Cloned protein antigens
have pluses and minuses
Pluses
•Easily manufactured and often relatively stable
•Cannot “revert” to recreate pathogen
Minuses
• Poorly immunogenic
• Post-translational modifications
• Poor CTL response
Viral vectors
have pluses and minuses
Pluses
• Infects human cells but some do not replicate
• Better presentation of antigen
• Generate T cell response
Minuses
•Can cause bad reactions
•Can be problems with pre-exisiting immunity to virus
•Often can only accommodate one or two antigens
Given that introduction,
should we search for a
vaccine against HIV and
how would we do so?
30 million deaths caused by HIV
33 million living with HIV/AIDS
2.7 million new infections in 2008
An effective vaccine could have a MAJOR
Impact on the future prognosis
iavi.org
This allows An
T cells
to vaccine
recognize
infected cells,
effective
must HIV
get around
the
HIV
uses
to evade
the immune
system
forstrategies
example,
and
even
internal
proteins
like reverse transcriptase can serve as antigens
This allows
T cellsmust
to recognize
HIV conserved
infected cells,
The vaccine
be able to target
essentialand
parts
of theinternal
viruses machinery
for and
example,
even
proteins
like reverse transcriptase can serve as antigens
Inaccessible epitopes
Antigenic escape
+ existence of many viral strains
This allows
T vaccine
cells to
recognize
The
must
act early inHIV
the infected
process cells,
Before the virus
firmly established
for example,
andbecomes
even internal
proteins
destroys the immune
system
like reverse And
transcriptase
can serve
as antigens
Integration and latency
Destruction of CD4+ T cells
Molecular Biology of the Cell Alberts et al
There are many possible
HIV Vaccine Approaches
Protein subunit
Synthetic peptide
Naked DNA
Inactivated Virus
Live-attenuated
Virus
Live-vectored Vaccine
Ramil Sapinoro, University of Rochester Medical Center
To begin we need to
ask some key questions
What should vaccine elicit?
To begin we need to
ask some key questions
What should vaccine elicit?
Neutralizing antibodies
to kill free virus
To begin we need to
ask some key questions
What should vaccine elicit?
Neutralizing antibodies
to kill free virus
OR
T cell response to
kill infected cells
To begin we need to
ask some key questions
What should vaccine elicit?
Neutralizing antibodies
OR
to kill free virus
T cell response to
kill infected cells
OR BOTH?
The biology of HIV provides some clues
Remember the long term non-progressors
Infected with a Nef mutant virus?
This would generate both
an antibody and a T cell response
Could this be used to generate a vaccine?
This prompted an experiment
that demonstrated
the feasibility of a vaccine
This prompted an experiment
that demonstrated
the feasibility of a vaccine
December 1992: Live attenuated SIV vaccine
Lacking the gene Nef
protected all monkeys for 2 years against
massive dose of virus
• All controls died
• cell mediated immunity was key
However, this approach is still
viewed as too risky to try on
human subjects
December 1992: Live attenuated SIV vaccine
Lacking the gene Nef
protected all monkeys for 2 years against
massive dose of virus
• All controls died
• cell mediated immunity was key
Another effort attempted to
use recombinant viral proteins as antigens
in an effort to generate neutralizing antibodies
VaxGen made two different forms
of gp120 from different HIV strains
and began human trials after chimp testing
Human vaccine trials are large
and very expensive
The trial was a failure,
with only minor effects seen
that were viewed
as statistically insignificant
NY Times
The next approach involved using
viral vectors to try to
also boost the T cell response
Many different viral vectors are
being investigated but this trial used
the human cold virus called
adenovirus
They actually used three
adenoviruses carrying three
different viral proteins
Gag
Pol
Nef
Early results suggested the immune
system was being stimulated
The hotly awaited results were
released at the 2007 AIDS Meeting
You be the judge—what happened?
This stunning failure
led to a re-thinking
of the approach
“DNA” vaccines are a novel approach
The field has decided in part to
go back to the basics:
how does HIV work
and how can we assess vaccine success?
Questions:
• For a vaccine what are the measures of protection?
• Can we overcome polymorphism?
• What are the key antigens?
• Attenuated or killed or neither?
• Is Mucosal immunity critical?
• Should it Prevent infection or prevent disease?
• What are the best Animal models
How does HIV kill cells anyway?
However trials continue,
but with more focus
on the details of how they affect immunity